The role of hydrodynamics should not be underestimated in any facet of the engineering sciences. The flow patterns within process units and their associated transfer lines have a significant impact upon mass, energy and momentum transport rates and reaction proficiency. Thus, system designs generally benefit from the identification of energy dissipation mechanisms and, thus, quantification of the intensity of mixing and contact efficacy. These are generally important factors in materials handling and manufacturing processes.
For example, the intensity of turbulence generally influences the size of particles that are dispersed throughout a fluid, the quality of an emulsion, and the residence time distribution profiles that determine progress and selectivity of chemical reactions. This is particularly apparent in the emerging nanotechnologies, where precipitation and crystallization processes have a significant impact on product quality. Furthermore, mixing characteristics influence and/or determine the performance of reaction vessels, at both laboratory and production scales, and properly designed/implemented mixing systems can permit and/or facilitate the use of continuous systems, in lieu of batch systems, to enhance productivity.
In terms of mixing technologies, cavitation has been used in industry for homogenization operations, i.e., to disperse suspended particles in colloidal liquids. Numerous engineering principles are involved with cavitation behavior (see, e.g., Christopher Earls Brennen, “Cavitation and Bubble Dynamics”, Oxford University Press (1995)). Although cavitation-based mixing is often employed with solids, it may not be the best choice for generation of nano emulsions and vesicle loading, as in drug chaperones. Cavitation can result in issues associated with materials of construction and/or scale-up issues for mixing device fabrication. In particular, by forcing a liquid through an annular opening that has a narrow entrance orifice with a much larger exit orifice, a dramatic decrease in pressure results in fluid acceleration into a larger volume and generation of cavitation bubbles. The surface upon which these bubbles collide (causing their implosion) is subjected to tremendous stresses. Thus, materials such as polycrystalline diamond and stainless steel are generally required.
Beyond mixing-related issues, a large number of compounds with potentially high pharmacological value fail to pass initial screening tests because they are too hydrophobic to be effectively formulated. Most formulation strategies aim at increasing the bioavailability of such drugs by particle size reduction, as described extensively in the literature. Such strategies include the production of emulsions, liposomes and functionalized chaperones by high shear processing, the production of nanosuspensions by milling, micronization or high shear processing, and the production of nanoporous materials.
Nano-emulsions, liposomes and other generalized cargo loaded systems can only encapsulate a limited amount of drug. Therefore, current approaches may not be the strategies of choice for drugs with high dosage demands. Nanosuspensions can deliver much larger amounts of drug in a smaller volume than solvent-diluted drug systems and, therefore, have a potential advantage as a formulation strategy.
Most often, nanosuspensions are produced by milling, micronizing or high shear processing. Thus, current methods for manufacturing nanosuspensions primarily rely on the reduction of particle size of drug powders in dry or wet formulations. Such “top-down” processes are generally slow, require repetitive processing cycles, and require substantial energy. Indeed, the targeted particle sizes, usually less than 0.5 microns, are often time consuming and expensive to produce, frequently requiring repetitive processing cycles/passes through the milling/high shear equipment to achieve desired particle size distributions.
Controlled crystallization of drugs is an alternative to the production of drug nanosuspensions through size reduction techniques for generating desired particle size distributions. Crystallization is a method that is used to produce fine chemicals and pharmaceuticals of desired purity and/or for the formation of a specific crystal polymorph with desired crystalline structure and associated properties. However, current crystallization techniques typically produce particles in the range of several microns which are not suitable for delivering highly hydrophobic drugs. More recently, methods for production of nanosuspensions through crystallization have been proposed, but they have not demonstrated the necessary productivity robustness. In particular, the newer procedures lack the control that is required at the various mechanistic steps of crystallization (nucleation rate through crystal morphology and stabilization), process scalability and general applicability.
The patent literature describes processing equipment for particle size control and manipulation. For example, commonly assigned U.S. Pat. Nos. 4,533,254 and 4,908,154 to Cook et al. describe processing systems and apparatus having particular utility in emulsion and microemulsion processing. Flow streams are forced under pressure to impinge in a low-pressure turbulent zone. The disclosed systems/apparatus include a plurality of nozzles that effect impingement of flow sheets along a common liquid jet interaction front.
More recently, commonly assigned U.S. Pat. Nos. 6,159,442 and 6,221,332 to Thumm et al. describe multiple stream, high pressure continuous chemical mixers/reactors that are adapted to: (i) individually pressurize different liquid streams to high pressure: (ii) individually monitor the flow of each liquid stream; (iii) provide a reaction chamber for receiving the pressurized liquid streams at high velocity; (iv) discharge a product stream which results from mixing of the pressurized liquid source material streams at high pressure and high velocity in the reaction chamber; and (v) control the rate of delivery of each reactant stream to the reaction chamber at a determined continuous stoichiometric rate. The Thumm et al. patents further disclose a closed loop control system that combines individual stream transducers to allow calculation of flow of each stream, computer hardware with control system application software, a hydraulic pressure/flow metering valve for each stream, and input/output connections to the computer hardware for the transducer data and meter valve drive. Of note, Thumm et al. contemplate pressurizing each reactant stream with a hydraulically-driven intensifier, wherein hydraulic pressure-flow metering valves regulate the intensifier's drive, thereby regulating the pressure and flow of each reactant stream.
Beyond the commonly assigned patent filings noted above, reference is made to the following patents/patent publications. Greenwood et al. disclose a sterilizable particle-size reduction apparatus in WO 2005/018687. Kipp et al. disclose methods/apparatus for generating submicron particle suspensions that involves mixing a solution that contains a pharmaceutically active compound that is dissolved in a water-miscible solvent with a second solvent to form a pre-suspension of particles and then energizing the mixture to form a particle suspension having an average particle size of less than 100 μm (see U.S. Patent Publications 2003/0206959 and 2004/0266890; U.S. Pat. No. 6,977,085).
In the field of crystallization, the patent literature includes various teachings from the pharmaceutical industry. For example, U.S. Pat. No. 5,314,506 to Midler, Jr. et al. discloses the use of impinging jets to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation in a continuous crystallization process. Nucleation and precipitation are initiated by utilizing the effect of temperature reduction on the solubility of the compound to be crystallized in a particular solvent (thermoregulation), or by taking advantage of the solubility characteristics of the compound in solvent mixtures, or a combination thereof. U.S. Pat. No. 5,578,279 to Dauer et al. discloses a dual jet crystallizer apparatus that includes a crystallization or mixing chamber having opposed angularly disposed jet nozzles. The nozzles deliver the compound to be crystallized and a crystallization agent. U.S. Pat. No. 6,558,435 to Am Ende et al. discloses a process for synthesis/crystallization of a pharmaceutical compound that involves contacting diametrically opposed liquid jet streams, such that the liquid streams meet at a point of impingement to create a vertical impingement film and create turbulence at their point of impact under conditions of temperature and pressure which permit reaction of reactive intermediates to produce a product. The jet streams are disclosed to have sufficient linear velocity to achieve micromixing of the jet stream constituents, followed by reaction and nucleation to form high surface area crystals. See also U.S. Patent Publication No. 2006/0151899 to Kato et al.
Despite efforts to date, a need remains for systems/apparatus and methods that are effective in producing nanoparticles. Systems/apparatus and processes for generation of nanoparticles in an efficient, continuous and reliable manner are also needed. Beyond nanoparticle processing, there remains a need for systems/apparatus and methods that are effective in facilitating various materials processing operations, e.g., reaction, emulsion and/or crystallization processes, by, inter alia, minimizing diffusion limitations to requisite interaction between reactants and/or crystallizing constituents. Still further, a need remains for systems and methods that yield desirable particle size distributions, morphology and/or compositions/phase purities through effective process design and/or control. Indeed, a need remains for systems and methods that effectively control interfacial reaction/contact between constituents to achieve desired processing results, e.g., to reduce the potential for undesirable side reactions. These and other needs are satisfied by the disclosed systems/apparatus and methods.